The potential of cardiovascular and non-cardiovascular therapeutic agents or drugs to cause prolongation of the QT (i.e., cardiac repolarization time between two ventricular sequences) interval of the electrocardiogram has been, and continues to be, a significant factor in the development of new therapeutic agents. Indeed, it is well established that a wide range of non-cardiovascular therapeutic agents that are not expected on the basis of their mechanism of action to prolong QT can produce a substantial number of serious cardiac events. Such agents belong to different pharmacological classes, such as psychotropic drugs (e.g., tricyclic-amitriptiline and tetracyclic antidepressants, phenothiazine derivatives, haloperidol, pimozide, risperidone and sertindole), prokinetic (e.g., cisapride), antimalarial medicines (e.g., halofantrine, quinine, and chloroquine), antibiotics belonging to several chemical classes (e.g., azithromycin, erythromycin, clarithromycin, spiramycin, pentamidine, trimethoprim-sulfamethoxazole and sparfloxacin), antifungal agents (e.g., ketoconazole, fuconazole and itraconazole), agents for treating urinary incontinence (e.g., terodiline), and certain histamine H1-receptor antagonist (e.g., astemizole, terfenadine and diphenhydramine).
These therapeutic agents, in certain very rare instances, can trigger life-threatening polymorphic ventricular tachycardias, such as torsade de pointes, often in the presence of additional factors favoring, directly or indirectly, proarrhythmic events. The relevant factors include congenital or acquired long-QT syndrome, ischemic heart disease, congestive heart failure, severe hepatic or renal dysfunction, bradycardia, electrolyte imbalance (e.g., hypokalemia due to diuretic treatment, hypomagnesemia, hypocalcemia, acidosis and intracellular Ca++ loading), intentional or accidental overdose, and concomitant treatment with ion channel blocking drugs or agents that inhibit the drug detoxification processes.
Several preclinical techniques have thus been employed to evaluate the cardiovascular effects of proposed therapeutic agents. The noted techniques to determine concentration of proposed therapeutic agents primarily comprise high performance liquid chromatography (HPLC) or other analytical assays that are generally limited to higher therapeutic agent concentrations unless pre-concentration or large volumes are employed.
It is, however, well known that the noted physiological analytical assays are often laborious, expensive, time consuming and frustrated by technical problems. Further, HPLC and/or assays may require hours to days to analyze samples and process data depending on the complexity and number of samples.
It is therefore an object of the present invention to provide a system and method for high-speed, economical in vitro analyses of therapeutic agents.
It is another object of the present invention to provide a system and method for in vitro analysis of low concentration therapeutic agents.
It is yet another object of the present invention to provide a system and method for correlating the electrophysiological effects of a proposed therapeutic agent over a broad concentration range.